Antibodies to receptor for advanced glycation end products (RAGE) and uses thereof

Abstract

The present application relates to antibodies, such as monoclonal antibodies, and in particular CDR grafted, humanized versions thereof, for the treatment and diagnosis of pain and other neuroinflammatory conditions associated with the Receptor for Advanced Glycation End Products (RAGE).

What is claimed is: 
     
       1. An isolated monoclonal antibody or antigen binding fragment thereof, wherein said antibody of antigen binding fragment thereof binds an epitope of a human Receptor Advanced Glycation END products (RAGE) molecule, said antibody or antigen binding fragment thereof comprising an antigen binding domain comprising:
 a) a heavy chain variable domain comprising complementary determining regions (CDR) 1, 2 and three wherein CDR 1, CDR 2, CDR 3 comprise the sequences of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively; and 
 b) a light chain variable domain comprising complementary determining regions (CDR) 1, 2, and 3 wherein the CDR 1, CDR 2, CDR 3 comprise the sequences of SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively. 
 
     
     
       2. The antibody or antigen binding fragment according to  claim 1 , wherein the antibody or antigen binding fragment further comprises a human acceptor framework. 
     
     
       3. The antibody or antigen binding fragment according to  claim 1 , wherein the antibody or antigen binding fragment comprises a heavy chain variable domain comprising the sequence of: SEQ ID NOs: 9, and a light chain variable domain comprising the sequence of: SEQ ID NOs: 13. 
     
     
       4. The antibody or antigen binding fragment according to  claim 1 , wherein the antibody or antigen binding fragment comprises
 (a) at least one framework mutation in the framework region of the heavy chain variable domain wherein the sequence of the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of: 62, 67, 68 and 69; and 
 (b) at least one framework mutation in the framework region of the light chain variable domain wherein the sequence of the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of: 63, 64, 65 and 66; or (c) combinations of (a) and (b). 
 
     
     
       5. A composition comprising the antibody or antigen binding fragment of  claim 1 . 
     
     
       6. An isolated monoclonal antibody or antigen binding fragment thereof which specifically binds to human Receptor Advanced Glycation End products (RAGE), comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13. 
     
     
       7. An isolated monoclonal antibody or antigen binding fragment thereof which specifically binds to human RAGE, wherein said antibody binds to the C2 domain of human RAGE protein having a sequence of SEQ ID NO:60 and wherein said antibody does not bind an epitope of the V domain or the C1 domain of human RAGE; wherein said antibody
 a) is a neutralizing antibody that is able to neutralize in vivo the effect of Ab1-40 on cerebral vasculature of mice; 
 b) does not bind to an epitope selected from the group consisting of SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79 and SEQ ID NO:80; and 
 c) binds a C2 epitope selected from the group consisting of selected from the group consisting of 235-336, 238-314, 229-340, 229-331 and 229-330 of human RAGE protein having a sequence of SEQ ID NO:60.